Balancing metabolism–control of weight gain, blood glucose levels and intestinal leakiness by alpha-lactalbumin-oleic acid complexes

Abstract

This study proposes a new molecular concept for the treatment of obesity and diabetes, using peptide-fatty acid complexes. Oral administration of the BAMLET complex reduced weight gain and hyperglycemia, in C57BL/6 mice with diet induced obesity. Intestinal glucose and lipid metabolism was broadly affected, including FGF19- and adiponectin-controlled gene networks. BAMLET treatment further targeted the glucose transporter GLUT2, reducing intestinal Slc2a2 expression and GLUT2 protein levels and targeting its glucose-binding pocket. Lowered GLUT2 levels and inhibition of glucose uptake in cellular models supported a potential in vivo effect on glucose uptake. BAMLET treatment further inhibited weight gain, adiponectin and leptin associated gene networks in chronically obese B6.Cg-Lepob/J mice and visceral and systemic adipose tissue growth was reduced in both backgrounds. Interactions with the oleic acid binding pocket of the AdipoR2 adiponectin receptor and the Ig-like domain of the leptin receptor were predicted in silico and confirmed by surface plasmon resonance. Relevance for chronic diabetes was further suggested by rapid effects of BAMLET in C57BL/6-Ins2Akita/J mice, with reversal of intestinal leakiness after three days and weight gain with continued treatment. The results identify BAMLET an orally available metabolic regulator and suggest a new, non-toxic approach to treating metabolic disorders.